Diseases of low bone mass, particularly osteoporosis, have gravely impacted society, causing massive disability. Current therapies for the restoration of bone mass are limited and focus primarily on the attenuation of osteoclast activity. The development of anabolic therapies that stimulate osteoblast activity and bone mass acquisition is essential; however, our understanding of the underlying mechanisms regulating osteogenic differentiation and bone formation is still incomplete. The work proposed in this grant aims to expand on our knowledge of the molecular mechanisms involved in bone mass acquisition by assessing the role of protein kinase C delta (PKC) in bone. Although PKC-/- mice exhibit reduced embryonic bone formation and a cell autonomous defect in osteoblast differentiation from embryonic limb primordial cultures, indicating involvement of PKC in embryonic osteogenesis, a role for PKC in post-natal osteoblast function and the molecular targets of PKC action in skeletal cells have not been established. Our lab has shown that PKC regulates the Runx2 activity, one of the master regulators of osteogenesis, thereby presenting a possible mechanism by which PKC can impact osteogenic differentiation. The central hypothesis of this grant application is that that PKC is a critical factor in multiple signaling cascades that converge on Runx2 and promote osteogenesis and increased bone formation. There are two specific aims to address this hypothesis. (Specific Aim 1) To examine the effect of PKC deficiency on osteoanabolic signaling downstream of multiple pro-osteogenic factors in vitro. (Specific Aim 2) To characterize the in vivo impact of loss of PKC in the cells of the osteoblastic lineage on post-natal bone formation. Cell and molecular biology, as well as in vivo genetic models, will be used to resolve key knowledge gaps regarding the role of PKC in bone. Defining these mechanisms will provide critical understanding into how PKC ultimately affects osteoblast function and bone mass acquisition. Hopefully, the knowledge gleaned from these studies will aid in the development of rational therapies against low bone mass disorders that stimulate the formation of bone by targeting pathways that converge on Runx2 via PKC modulation.